@article{APS9254,
author = {Xiao-dan GUO and Guang-long SUN and Ting-ting ZHOU and Xin XU and Zhi-yuan ZHU and Vatcharin RUKACHAISIRIKUL and Li-hong HU and Xu SHEN},
title = {Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance},
journal = {Acta Pharmacologica Sinica},
volume = {37},
number = {10},
year = {2017},
keywords = {},
abstract = {Aim: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice.
Methods: Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg−1·d−1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains.
Results: LX2343 (5–20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aβ pathology in their brains.
Conclusion: LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aβ production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/9254}
}